This invention relates to radioactive implants, methods of making them and methods of using them.
It is known to use external beam supervoltage or megavoltage conventional fractionated radiation therapy to treat subclinical microscopic metastases in surgically undisturbed lymph node chains and to sterilize the postoperative tumor bed after the tumor is grossly excised. The uses of external beam radiation techniques have a disadvantage that they are not able to safely treat solid tumors because the solid tumors require an intensity of radiation that is harmful to the surrounding normal tissue.
It is also known to implant radioactive sources directly into solid tumors for the destruction of the tumors in a therapy referred to as brachytherapy (short-range therapy). This therapy permits the application of larger doses of radiation.
In the prior art brachytherapy, the sources are generally implanted for short periods of time and generally are sources of high radiation intensity. For example, radium needles and iridium-192 ribbons have been implanted into tumors (interstitial brachytherapy) or radium-226 capsules and cesium-137 capsules have been placed into body cavities such as the uterus (intracavitary brachytherapy).
The prior art interstitial brachytherapy treatment using radium needles has several disadvantages, such as for example: (1) dosimetry is difficult and imprecise; (2) local failures are caused, mainly by the large size of the radium needles (approximately the size of a lumber nail); (3) it is difficult to implant an adequate number of the needles uniformly throughout a tumor to produce homogeneous irradiation because they are large sources; and (4) the needles can only be left in place temporarily, and must be surgically removed.
It is known to implant iodine seeds temporarily or permanently. The prior art iodine seed consists of the radionuclide adsorbed onto a carrier which is placed into a metal tube that is welded shut. It has the disadvantages of: (1) being relatively large to be safely implanted in large numbers in the human body; and (2) due to its construction, producing inhomogeneous radiation.
The prior art iridium seeds in ribbon consist of solid iridium wire cut into pieces and placed in plastic tubing, which is then implanted into accessible tissues temporarily for several days. These seeds work well, but because they must be removed, their application is limited to a few accessible body sites. Also, they only come in one energy.
The prior art radium-226 intracavitary sources and cesium sources consist of metal cylinders containing radium salts or cesium. They have several disadvantages, such as for example: (1) dosimetry is difficult and imprecise; (2) they are bulky and difficult to use; (3) it is difficult to implant or otherwise insert an adequate number of the cylinders in the proper locations to produce homogeneous irradiation because they are large sources; (4) the cylinders can only be left in place temporarily, and under some circumstances, must be surgically removed; and (5) general anesthesia is required to dilate the cervix sufficiently to place a source in the uterus.
The applications of brachytherapy are still severely limited by the unavailability of a wide range of implantable radioactive sources that have a wide range of gamma energies (radiation energy is related to the volume irradiated) and varying half-lives (radionuclide half-life affects tumor dose rate, radiobiology, and normal tissue effects). Also the limited number of sources currently available are still physically unsatisfactory in their construction. There are few low energy limited lifetime radioactive seeds such as gold-198 and iodine-125 seeds that may be permanently implanted into solid cancers.
It is also known to apply heat to tumors by implanting metals that may be heated by radio frequency radiation and to move heatable or radioactive members about magnetically for positioning them without excessive surgery. This is especially significant in the treatment of highly vascular tumors. The existing hyperthermia radio frequency treatment is not well adapted for easy combination with endocurietherapy.
Accordingly, it is an object of the invention to provide novel radioactive implants.
It is a still further object of the invention to provide a novel electron-producing beta-seed.
It is a still further object of the invention to provide a perfectly spherical tantalum, tungsten, gold, platinum casing or compound tungsten carbide, tantalum carbide casing over a radioactive microspherical substrate when the radioactive material produces high energy gamma rays.
It is a still further object of the invention to provide a perfectly spherical titanium, hafnium or zirconium metal casing or a compound casing of titanium carbide, titanium nitride, titanium conbonitride, hafnium nitride or zirconium nitride over a radioactive microspherical substrate when the radioactive material produces low energy gamma rays.
It is a still further object of the invention to provide a perfectly spherical diamond casing over a radioactive microsphere when the radioactive material produces beta rays.
It is still further object of the invention to produce a novel low-energy permanent multilayered radioactive microsphere.
It is a still further object of the invention to provide a novel tissue-compatible (absorbable and non-absorbable) surgical fabric that contains multiple radioactive seeds to facilitate rapid implantation of a large number of radioactive seeds.
It is a still further object of the invention to provide a novel ribbon containing multiple low energy permanent multilayered radioactive microspheres.
It is a still further object of the invention to provide a novel multilayered low energy permanent or temporary radioactive wire that may be permanently or temporarily implanted into human tissues and that safely delivers low energy.
It is a still further object of the invention to provide a novel implant that safely delivers energy at levels less than or equal to 100 KeV average gamma energy to tumors at a low rate in less than 130 days to produce tumoricidal radiation doses that are 2.3 to 5.7 times higher than the maximum doses permissible with reasonable safety by modern megavoltage external beam radiation therapy techniques.
It is a still further object of this invention to produce a radioactive seed which has the clinical result of reducing the complication rate of treatment while increasing the local cure rate by allowing safe delivery of very high radiation doses to solid human tumors.
It is still further object of the invention to produce an improved radioactive seed, ribbon containing multiple seeds, or radioactive wire which may be permanently implanted into human tissues and safely deliver high energy (greater than 100 KeV average gamma energy) tumor irradiation at an average dose rate less than 1.50 Gy/hour (Gray/hour-one Gray is equal to 100 rad) in less than 15 to 20 days.
It is a still further object of the invention to provide a novel technique for making an improved radioactive seed, seed ribbon, or radioactive wire which may be temporarily implanted into human tissues by after-loading tubes or by implanting interstial needles.
It is a still further object of the invention to produce a novel multilayered radioactive microsphere, ribbon microsphere, or multilayered radioactive wire, which emits electrons or beta particles and have casings which are substantially transparent to electrons.
It is a still further object of the invention to provide a radioactive seed having a shape that is spherical rather than cylindrical to make it less likely to jam in an auto-feeding tissue implantation gun.
It is a still further object of the invention to increase the clinical utility and safety of the radioactive seed by making it significantly smaller in diameter to permit tissue implantation with thinner gauge needles.
It is a still further object of the invention to improve upon the uniformity of the radioactive coat used in radioactive seed production.
It is a still further object of the invention to produce a radioactive seed which contains multiple coats which have specialized purposes.
It is a still further object of the invention to produce a radioactive seed which contains a diffusion barrier coat over the radionuclide layer.
It is a still further object of the invention to produce a radioactive seed which contains a coat that enables visualization of the seed in tissue such as by magnetic resonance imaging (NMR, MR) or X-ray or single positron resonance (SPECT) or positron emitting tomography (PET) or the like.
It is a still further object of the invention to produce radioactive seeds that contain different magnetic resonance imaging marker coat to enable separate individual identification of one type of seed from another type of seed when seeds containing different radionuclides are implanted into the same tumor.
It is a still further object of the invention to produce an outermost seed coat which reduces friction, adds coloring for seed type identification, increases hardness and durability, and increases tissue compatibility and corrosion resistance.
It is a still further object of the invention to produce a more miniaturized intracavitary source that may be placed into the uterus without endocervical dilation or into the bladder with minimal trauma to the urethra and is available in a wide range of energies and isotopes.
It is a still further object of the invention to provide a radioactive seed that can be raised to a selected temperature by remotely radiated energy for hyperthermia.
It is a still further object of the invention to provide a radioactive seed that can be moved by remotely originated radiant energy.
It is a further object of the invention to provide novel techniques for manufacturing radioactive implants.
It is a still further object of the invention to provide techniques for manufacture of radioactive seeds containing a wide variety of radionuclides with different energies and half-lives.
It is a still further object of the invention to provide techniques for manufacturing a wide variety of radio-nuclides including those useful for permanent implantation into human tissues, those useful for temporary removable interstitial needle or ribbon implantation into human tissues, and those useful for temporary intracavitary irradiation.
It is a still further object of the invention to mass manufacture microspherical seeds less than 0.40 millimeter in diameter that may contain a therapeutic amount of radioactivity, a hard tissue-compatible protective coat, and several special purpose coats.
It is a still further object of the invention to provide a novel technique for manufacture of multiple radioactive seeds connected by a ribbon or wire to facilitate rapid implantation of multiple seeds.
It is still further object of the invention to provide a novel technique for manufacture of multilayered radioactive wires that contain a wide variety of different radionuclides for use in temporary removable tumor implants.
It is a still further object of the invention to manufacture a novel small-diameter (less than one millimeter) high-activity intracavitary source using any of a variety of different radionuclides.
It is a still further object of the invention to present a novel method for incorporation of a radionuclide into a seed during manufacture of the seed.
It is a still further object of the invention to provide a novel method for incorporation of a non-radioactive elemental isotope into a seed during manufacture of a seed that will later form the desired radioactive isotope when the finished seed is bombarded with neutrons.
It is a still further object of the invention to provide a method for making a perfectly spherical titanium casing over a radioactive microspherical substrate when the radioactive material produces low energy gamma rays.
It is a still further object of the invention to provide a less expensive seed by eliminating the need for human or mechanical assembly of separate parts and welding of individual seeds.
It is a still further object of the invention to provide an effective low cost method for large-scale mass-manufacture of high quality radioactive seeds for use in implantation of human tissues and to make the seeds readily available for use in large numbers of patients on a daily basis.
It is still further object of the invention to provide means of modified manufacturing processes which allows great versatility in manufacturing seeds of a variety of designs containing different combinations of types of radionuclides, metal and alloy coats, and elemental nonmetallic as well as compound hard coats.
It is a still further object of the invention to introduce a versatility of manufacturing process that permit manufacture of improved seeds which have varied physical characteristics including different average gamma radiation energies and different average lifetimes.
It is a still further object of the invention to provide a combination of manufacturing techniques that permit optimally matched seeds for the physical location and radiobiology of the tumor type or cancerous tissue they are designed to destroy.
It is a still further object of the invention to provide novel method for production of radioactive microspheres, ribbon microspheres or wires in which the radioactive component is incorporated into the microsphere by the reaction of an excited radionuclide gas with a target material produced by reactive coating techniques.
It is a still further object of the invention to provide a novel method for production of radioactive microspheres, ribbon microspheres, or wires in which the radioactive component is incorporated into the microsphere by sputtering, laser ablation, cathodic arc plasma deposition or curvilinear cathodic arc plasma deposition from a target material consisting of a radioactive dielectric compound material or a radioactive metal.
It is a still further object of the invention to provide novel techniques for using radioactive implants.
It is a still further object of the invention to provide a novel technique for eliminating the radiation dose anisotropy problems characteristic of the tungsten end-welded cylindrical radioactive seeds.
It is a still further object of the invention to reduce the danger of radioactive contamination of the hospital environment.
It is a still further object of the invention to reduce the danger of case rupture of the radioactive seed by eliminating the free space between the radioactive component and the casing.
It is a still further object of the invention to reduce the danger of radiation exposure to personnel involved in seed assembly.
A still further object of the invention is to produce a radioactive seed which has the clinical result of reducing the complication rate of treatment while increasing the local cure rate by allowing safe delivery of very high radiation doses to solid human tumors.
It is a still further object of the invention to provide a novel therapy for necrosis of tumors.
It is a still further object of the invention to provide a novel therapy which combines low dose continuous radiation with higher dosage radiation for the destruction of tumors.
It is a still further object of the invention to provide a novel therapy for the incorporation of low energy implants into a tumor with externally applied high energy treatment to destroy a tumor.
It is a still further object of the invention to provide a novel therapy in which cancer cells are biased toward a sensitive state and then irradiated for a short period of time while in the sensitive state.
It is a still further object of the invention to produce a radioactive seed which has the clinical result of serving as a radiation sensitizer when implanted prior to administration of conventional external-beam radiation therapy and which delivers continuous low dose rate radiation to block tumor cells in the most radiation sensitive portions of their cell cycle.
According to the above and further objects of the invention, a one-piece solid spherical seamless multilayered radioactive seed, herein sometimes referred to as a multilayered radioactive microsphere includes a spherical radioactive thin layer with a therapeutic amount of activity. The spherical seed has several desirable characteristics such as for example: (1) its contents may provide up to 1000 millicuries of activity and a completely spherical photon fluence without significant anisotropy; and (2) there is no free space between the radioactive component and the casing.
In a preferred embodiment, it includes a microspherical central marker, a spherical radioactive thin coat containing a therapeutic amount of activity, a spherical diffusion barrier coat, an optional special purpose spherical coating designed to enhance diagnositc imaging, a thick spherical (up to 0.10 mm) protective coating containing the inner coats, and an optional thin outermost special-purpose coat in the order listed. The multilayered radioactive microsphere contains: (1) no free spaces or cavities; and (2) no end-welds. The central marker or special coat for imaging may be selected for X-ray, PET, SPECT or MR or any other type of imaging.
The multilayer radioactive micropsphere radionuclide is selected for the desired purpose. For example, for a first group of purposes, the radionuclide has a weighted average gamma energy of less than 100 KeV, with a half-life of less than 130 days. This multilayer radioactive micropsphere is referred to as a low energy permanent multilayered radioactive microsphere for permanent interstitial implantation into human tumor tissues. The corresponding multilayer radioactive microsphere with a gamma energy greater than 100 KeV is referred to as a high energy permanent multilayered radioactive microsphere for permanent interstitial implantation into human tumor tissues. Preferably, its half life is less than 15 to 20 days.
For a second group of purposes, the radionuclide has a weighted average gamma energy greater than or equal to 100 KeV, with a half-life of greater than 15 to 20 days, or an average energy less than 100 KeV and a half-life of greater than 130 days. This multilayered radioactive microsphere is referred to as a temporary removable multilayered radioactive microsphere for temporary removable interstitial implantation into human tumor tissues.
For a third group of purposes, the radionuclide emits a high energy electron particle without significant high-energy gamma-ray, component. This multilayer radioactive microsphere is referred to as an electron-producing or beta multilayered radioactive microsphere for permanent or temporary removable interstitial implantation into human tumor tissues.
The shape, size and packaging of the multilayered radioactive seeds are appropriate for their purposes, such as being a microsphere having a diameter of 0.40 millimeters or less for use in injection equipment or in the case of wire or ribbon, having a similar diameter to permit interstitial tissue implanation through a regular 21 gauge needle or through a thin-walled 22 gauge needle.
The radioactive coat of the multilayered radioactive microsphere comprises one or more of: (1) a metal such as palladium-103, gold-198, thulium-170, or chromium-56, a mixture of metals, a mixture of compounds including radioactive metals or radionuclides, or a radionuclide bound to a metal; or (2) a dielectric radioactive element such as arsenic-73, yttrium-90, or iodine-125 or compound dielectric materials containing one non-radioactive and one radioactive component such as zirconium iodide Zr(I-125)4, hafnium iodide Hf(I-125)4, titanium iodide Ti(I-125)2, silver iodide-125, thulium bromide-170, magnesium arsenide-73, potassium iodide-125, rubidium silver iodine-125, or copper iodide-125; or (3) any combination of radioactive dielectric compounds; or (4) two or more radioactive components, such as for example arsenic-73 and di-iodide-125, arsenic-73, selenide-75, or palladium-103 and iodide-1 25.
The radioactive coat may also be formed in different configurations such as by being laminated together with a non-radioactive high boiling point or hard metal by sputtering, laser ablation ion plating, ion beam sputtering, or cathodic arc deposition; (2) by being uniformly covered by a spherical diffusion barrier that may consist of a coat of single metals such as gold, tantalum, palladium, and titanium or several layers of metals or compounds such as titanium-palladium-gold, gold-titanium, titanium nitride (TiN), zirconium nitride (ZrN), titanium carbide (TiC), titanium (T), tungsten/titanium (W/T), tungsten carbide (WC), tungsten nitride (WN), tungsten/titanium nitride (WTN), hafnium nitride (HfN), Hafnium carbide (HfC), zirconium carbide (ZRC), Vanadium carbide (VC), boron carbide (BC), tungsten boride (WB) or diamond. The diffusion barrier may be covered by a uniform spherical thick (up to 0.10 millimeter) protective coat.
Either inside the radioactive layer or over the diffusion barrier inside the protective coat, there may be an inner spherical uniform special purpose coat. This special purpose coat may be used to enhance imaging of the multilayer radioactive microsphere by means of conventional radiographs or MR, CT, SPEC or PET imaging. For example, the special spherical inner coat may consist of gadolinium for magnetic resonance imaging of the multilayer radioactive microsphere.
The spherical thick outside protective coat may be composed of: (1) a resistant human tissue-compatible metal which also has low atomic weight to minimize X-ray shielding such as titanium or other corrosion-resistant metal alloy such as stainless steel; or (2) a resistant human tissue-compatible metal compound (using reactive nitrogen, oxygen, methane, or carbon monoxide gases during coating to form carbides, nitrides, or carbonitrides of transition metals or other metals) such as titanium carbide, titanium nitride, titanium carbonitride, titanium aluminum nitride, zirconium nitride and hafnium nitride; or (3) a resistant human tissue-compatible metal coating less than 0.1 millimeters thick which has a high atomic weight such as tantalum, platinum or gold or the corresponding compounds of tungsten carbide, tantalum carbide, or platinum oxide; or (4) a human tissue-incompatible metal coating which is covered by a-tissue-compatible thin coating.
If a tissue-compatible outermost thin coat is included it may be sputtered diamond, tantalum, tungsten or titanium and should overlay the thick protective metal casing. In this case, the more toxic but low atomic weight metals such as beryllium, vanadium, nickel and boron nitride may be used as the thick protective casing. The thin outer coats may consist of a special-purpose coats designed to enhance physical properties of the seed such as diamond or diamond-like carbon, platinum, or tantalum. These coats individually enhance the multilayer radioactive microsphere by adding hardness, and corrosion resistance.
The outermost thin coat may also be used to produce different seed identification colors. For example, the outermost thin coat may consist of titanium nitride (TiN) to produce a golden color, titanium carbonitride (TiCN) to produce a brown color, titanium aluminum nitride (TiAlN) to produce a black color, titanium carbide (TiC) to produce a gray color, zirconium nitride (ZrN) to produce a silver-yellow color, and hafnium nitride (HfN) to produce a yellow-green color.
The central sphere or other coats may be formed of a material that is heatable by remotely radiated energy for hyperthermia and/or a material that enables force to be applied to the seed to move it around using externally radiated energy to avoid damage to tissue. For example, ferrogmagnetic materials may be used that heat by induced radio frequency energy to the Curie temperature and have a Curie temperature appropriate for hyperthermia, such as for example, 50 degrees Centigrade. Moreover, a ferromagnetic material may cause movement of the seed by externally applied magnetic fields.
In one form of therapy using the multilayer radioactive microsphere, multiple low activity multilayer radioactive microsphere""s (between 30 and 300) are permanently implanted into a human tumor at approximately 1 cm (centimeter) intervals throughout the volume, thus producing continuous low-dose-rate low energy irradiation at less than 1.0 Gy/hour and preferably less than 0.20 Gy/hour and delivering minimum doses of 80 to 400 Gy to the tumor volume over the average lifetime of the multilayer radioactive microsphere.
In another form of therapy using the multilayer radioactive microsphere (MRM), several (1 to 10) high activity multilayer radioactive microsphere""s are permanently implanted into a human tumor producing continuous low-dose-rate low energy irradiation at less than 1.0 Gy/hour and preferably less than 0.20 Gy/hour and delivering minimum doses of 80 to 400 Gy to the tumor volume over the average lifetime of the multilayer radioactive microsphere.
In still another form of therapy, a long term low energy radiation is applied to a tumor followed by a short term high energy radiation. In one embodiment, the low energy radiation serves as a radioactive sensitizer which blocks tumor cells in the most radioactive sensitive portions of their cell cycles and the high energy beam is applied when the tumor cells are sensitive.
In one embodiment, a low intensity radioactive seed is implanted to provide the long term low intensity radioactivity and external radiation beam is used for the high intensity. In this embodiment, the relatively low radiation dose of between 40 to 80 Gray is delivered substantially continuously at a low dose rate over a time period of 30 to 200 days and preferably approximately 30 days. Either temporary or permanent implantation of one or several seeds may be used to accomplish this purpose. This low dose-rate radiation blocks the tumor cells in their most radioactive sensitive parts of their cell cycles. These are optimally killed at the time of delivery of a conventional daily fractionated radiation given over two minutes each 24-hour period for five days a week.
To avoid leakage of radioactive material, a layer of metal that chemically reacts with the material in the radioactive layer may be sputtered or otherwise coated over the radioactive material and before the defusion layer. For example, silver may be sputtered as an even coat over radioactive iodide layers to reduce leakage. The density and uniformity of the barrier layer is maximized by coating under the lowest pressure possible and by introducing maximum energy while avoiding welding of the microspheres together.
To make multilayer coatings of a microsphere for mass-production of the multilayer radioactive microsphere, a microspherical substrate is coated with multiple uniformly-spherical coats which consist of a radioactive coat, a thick protective coat (up to 0.1 millimeter), and in some embodiments, a diffusion barrier coat, an optional special-purpose imaging-enhancement coat and an optional special purpose outer thin coat.
The microsphere is adapted to be made in a manufacturing process that eliminates the need for assembly of separate seed parts and welding of titanium tubing containing the radioactive material because the multilayer radioactive microsphere is constructed by electronic means. In the processes used: (1) one-hundred to one-thousand multilayer radioactive microsphere""s can be produced in a single batch or run of the coating equipment; and (2) the design of the multilayer radioactive microsphere can be easily modified or its components or type of radionuclide easily changed by changing either the target materials, coating atmosphere or operational parameters of the coating process.
In manufacturing the coats, existing coating techniques are used. In one embodiment, one or more radioactive dielectric or metal materials are used as a target in a sputter-deposition, laser ablation, or cathodic arc plasma-deposition system to produce a stable radioactive radionuclide-metal coat upon microspherical substrates, ribbon-mircospheres, or wire substrates. Moreover, combinations of radioactive and non-radioactive materials may be used.
The deposition of the radionuclide coat or laminate of a radionuclide and high-boiling point metal must be uniform. The peak-to-valley height variation in this coating should not exceed plus or minus 400 Angstroms. It should have high quality in terms of uniformity, spherosity and not have macroparticles, holes or other defects.
Other thin layers should be uniform but are not as sensitive to the lack of uniformity. Those layers are the diffusion barrier coat and in some embodiments, imaging coats. A relatively thick protective coat such as one of 0.05 millimeters is less critical as to uniformity.
All of these substrates are applied by processes which bond so there are substantially no voids in the member. Generally, sputtering is preferred with the thicker layers utilizing higher power and larger targets and the thinner layers smaller targets and lower power so that the same apparatus may be used for the different coats and all be applied with reasonable speed in spite of the difference of thicknesses by energizing different targets at different times. Thicker coats might also be applied by cathodic arc plasma-deposition techniques although these techniques do not usually apply with the same uniformity. In a few embodiments, electrolysis is suitable although electrolysis in most applications does not provide as uniform a surface area as sputtering and in the case of microspheres, it is difficult to obtain uniformity on all sides.
Generally, fabrics, wires and ribbons may be plated while they are suspended in a vacuum but the microspheres require a levitating device such as a vibrator that bounces them so that they will be coated on all sides. The most uniform coats are applied by vacuum methods but there are other methods which can create the uniformity and intimate contact of the coats desired in these products. Because some of the radionuclide coats are soft, low boiling point metals, special precautions can be taken to prevent the microspheres from being welded together. One such precaution is to combine the low boiling point radionuclide with a higher boiling point metal in interleaved areas or concomitantly. Injection of 1% to 5% of an electronegative gas such as oxygen gas will present microsphere vacuum welding. In another embodiment, gaseous radionuclides are bound by combining them with a metal during the coating process such as by sputtering the radioactive nuclide gas together with a metal in an argon atmosphere to form a coat of a compound combining the radionuclide and the metal.
The multilayer radioactive microsphere radio active microspherical substrate coat may be produced by one of several processes, such as: (1) from a radioactive metal target by dc sputtering; or (2) by radio frequency or magnetron sputtering using a radioactive dielectric target; or (3) by reactive sputter-deposition in an excited radioactive gas producing a coat which is a radioactive compound of the radioactive gas and the sputtered target material; or (4) by reactive cathodic arc plasma deposition in an excited radioactive gas producing a coat which is a radioactive compound of the radioactive gas and the sputtered target material; or (5) by reactive ion beam sputtering using a cathodic arc ion source in an excited radioactive gas producing a coat which is a radioactive compound of the radioactive gas and the sputtered target material; or (6) by reactive ion-platingusing an electron-beam source in an excited radioactive gas producing a coat which is a radioactive compound of the radioactive gas and the sputtered target material; or (7) by cathodic arc plasma deposition using a radioactive dielectric target; or by (8) laser ablation of the target metal in the presence of a radioactive gas forming a radioactive metal compound on the substrate.
A radioactive dielectric coated planar metal target for use in cathodic arc plasma deposition or for use in rf or magnetron sputtering may be made by coating a metal planar substrate with a radio-active dielectric compound using reactive dc, rf, or magnetron sputtering, reactive cathodic arc plasma deposition, reactive ion-beam sputtering, or reactive ion plating wherein the radioactive compound coat is produced from an excited radionuclide gas and a non-radioactive metal target.
To optimize mass-production manufacture of the multilayer radioactive microsphere a two step process is used employing sputter deposition with a radioactive dielectric or metal target, or reactive sputter deposition in a radionuclide gas to produce a uniform radioactive coat over a microspherical substrate followed by ion-plating, or ion-beam self-sputtering using a cathodic arc ion source, or cathodic arc plasma deposition or high-energy high deposition rate sputtering using a large sputter gun, to produce the remaining coatings and spherical thick protective metal coatings over the radioactive microspheres.
In another method for mass-production manufacture of the multilayer radioactive microsphere consisting of a one-step process employing reactive cathodic arc plasma deposition, reactive laser ablation deposition, or reactive ion beam sputtering using a cathodic arc ion source, or reactive ion plating all carried out in an excited radionuclide reactive gas/inert gas mixture to form a smooth spherical stable compound radioactive coating over a microspherical substrate, followed by use of either ion plating, ion beam sputtering, cathodic arc deposition or laser ablation to produce the remaining coatings and spherical thick protective metal coatings over the radioactive microspheres.
In still another optimized method for mass-production manufacture of the multilayer radioactive microsphere consisting of a one-step process employing cathodic arc plasma deposition using a radioactive dielectric or metal target to produce a radioactive coat over a microspherical substrate, followed by use of cathodic arc plasma deposition to produce the remaining coats and spherical thick protective metal coats over the radioactive microspheres.
To eliminate vacuum welding between levitated microspheres, soft low boiling point elements (that are likely to vacuum weld) are laminated with hard, high boiling point elements (that are unlikely to vacuum weld). The microspherical substrates may be biased to improve reactive deposition efficiency using a reactive gas in a sputtering, ion plating, ion beam sputtering, or cathodic arc deposition. Moreover, levitation is improved to further reduce welding by creating a capacitive bias effect with the bouncing pan being electrically isolated from the rest of the sputtering apparatus. To create the capacitive bias effect, the bouncing pan may be an insulating ceramic with a conductive liner or may be a conductor coated with an insulating material. The material is connected by a conductor to a source of potential to create the bias. The bouncing pan is driven at high power by an ultrasonic transducer that is tuned to a frequency slightly different than the resonant frequency of the system.
Several embodiments of therapeutic devices can be formed. In one embodiment a ribbon-multilayer radioactive microsphere substrate has microspheres attached to the ribbon prior to coating. Coats are then applied to form a ribbon surface for rapid implanting of seeds. The coats may vary at different locations to enable in some embodiments, a contoured radiation pattern. In another embodiment, a multilayered radioactive wire design has a coat applied to a wire substrate by means of sputtering, laser ablation ion plating, ion beam sputtering, or cathodic arc deposition. The radioactive material is differentially deposited onto a substrate wire in such a manner that variable activities are deposited per unit length in a controlled fashion to match a computerized treatment plan.
In other embodiments, absorbable or non-absorbable surgical fabrics containing multiple multilayer radioactive microspheres spaced apart on the fabric or miniaturized intracavitary sources of radioactivity composed of multiple multilayer radioactive microsphere""s are fabricated. Coats are applied in successive layers on the fabric and microsphere substrate or only on the microsphere substrate using masking in forming a fabric. Also, finished microspheres can be embedded during manufacture of a cellulose fabric. To form small intracavity sources, microspheres are first formed by sputtering or other such manufacturing technique and then afterloaded into containers that are welded shut. In still another embodiment, an ocular applicator is constructed in which radioactive multilayers are deposited on the active surface by means of sputtering, ion plating, ion beam sputtering, cathodic arc deposition, or laser ablation.
Some of the embodiments that are fabricated enable improvement in other known techniques. For example, a modified multilayer radioactive microsphere that contains a ferromagnetic alloy that may be inductively heated in situ by applied radio frequency radiation may be formed. The coat passes through a Curie transition at temperatures useful for clinical hyperthermia and stops receiving inductive heating, thus maintaining the proper temperature. Also, a solid multilayered radioactive needle for temporary removable implants incorporates a wide variety of radionuclides and is thinner than a conventional radium-containing needle, thus enabling its use without major tissue trauma and improving the implant geometry.
The radioactive single seed design of this invention has several advantages such as: (1) it is smaller than prior art radioactive seeds and is spherical thus permitting a wider range of uses and easier use with less traumatic insertion into human tissues; (2) it is stronger and has high structural integrity and is thus safer; (3) it is symmetrical and uniform and thus produces a symmetrical radiation field as shown by symmetrical dosimetry; (4) it may be constructed using a wide variety of isotopes of differing energies and half-lives selected for specific applications, thus permitting optimization of the radiobiology of the type of cancer being treated; (5) it is inexpensive; and (6) in clinical practice, it permits safe delivery of radiation tumor doses that are two to five times higher than that achieved with external beam irradiation; and (7) the different multilayered radioactive microspheres can be identified by their different imaging contrast agent coats or center substrate.
In use, the microspheres have several advantages such as: (1) an effective modality for treatment is provided by combining a relatively low continuous dose of radiation by multilayer radioactive microspheres implanted in a tumor at any anatomic location and which serve as radiosensitizers so that a short conventional course of external-beam radiation therapy is much more effective; (2) radiation dose localization is improved beyond that achievable with the low energy permanent gamma-ray seeds by use of an electron-producing seed because electron dosimetry is more localized than X-ray dosimetry; (3) different types of multilayered radioactive microspheres with different half-lives and photon or electron energies can be implanted into a tumor in the same operation to optimize tumor therapy; and (4) the use of permanent implantation of short-lived seeds rather than temporary-removable implants eliminate exposed tubes which penetrate the skin surface and serve as a route for infection over many days.
There are also advantages from the composite designs that can be produced using the spheres, such as for example: (1) ribbons and a tissue-compatible fabric containing seeds useful for rapid surgical implantation may be produced; (2) the thin ribbon design containing multiple seeds allows rapid implantation of multiple seeds using a hollow interstitial needle; (3) a tissue-compatible surgical fabric containing multiple radioactive seeds allows rapid intraoperative implantation of a sheet of evently spaced radioactive seeds; and (4) the various surgical procedures and devices used for implantation of radioactive seeds provide better adaptability to a patient""s needs.
There are also advantages from a wire multilayered radioactive design such as: (1) it may be cut up into pieces and placed into afterloading catheters or into nylon or polyethylene ribbons for temporary removable implants or placed inside appropriate containers to construct various intracavitary sources; (2) it has the advantages of being flexible or remain as a long needle, with or without an added sleeve for temporary implanting.
When encapsulated: (1) the multilayered radioactive microspheres simplify intracavitary therapy because smaller intracavitary capsules can be construed using multiple small-diameter seeds of the present invention; (2) a wide variety of radionuclides with energies varying from very low to very high can be incorporated into composite intracivitary sources by sealing multiple multilayered radioactive microspheres of one or several types into an appropriate container; (3) use of low energy intracavitary sources composed of low energy multilayered radioactive microspheres allow selective shielding of adjacent vital structures such as rectum and bladder using relatively thin high atomic weight foils placed over the intracavitary sources or source holders.
There are also several advantages related to manufacturing the radioactive implants such as: (1) it permits mass production of a variety of designs without need of assembly of separate (radioactive) parts; (2) changes in seed composition may be made easily; (3) it permits customized manufacture of multilayered radioactive microspheres, multilayered radioactive wires, ribbon-multilayered radioactive microspheres or optical plaques optimized for individual tumor types; (4) manufacture of new models of multi-layered radioactive microspheres, multilayered radioactive wires and ribbon-multilayered radioactive microspheres can be accomplished as needed by simply changing deposition parameters, or by changing the type, thickness, and layering of deposited elements using the same deposition equipment; (5) it permits construction of seeds containing many optional different types of laminated materials such as imaging contrast agents, colored seed identification markers, or supplemental protective outer layers; (6) use of the high energy processes of sputtering, laser ablation ion-beam sputtering, cathodic arc or curvilinear cathodic arc plasma deposition, reactive deposition, and ion plating increase the hardness of metals coated in this manner compared to the bulk materials; and (7) the controlled variable deposition of radioactive material per unit length or per unit surface area permits customized manufacture of brachytherapy sources to exactly match the requirements of 3-dimensional computerized brachytherapy treatment plan.
The ability to provide a variety of half-lives and intensities of implants has several advantages, such as for example: (1) the smaller permanent seeds permit implantation of a greater number of seeds in more body sites using thinner needles with less risk of complication; (2) a combination of short-acting high-energy and long-acting low energy seeds can be implanted in the same procedure; (3) under some circumstances repeated implantation of seeds with short half-lives may be used instead of repeated temporary removable implant procedures thus reducing the risk of infection associated with temporary removable implants; (4) high energy short-lived seeds provide results equivalent to a temporary removable implant, but they may be applied to sites not accessible to temporary removable implantation; (5) short-lived seeds may be implanted as a xe2x80x9ctumor-boostxe2x80x9d, replacing and improving upon a xe2x80x9ctumor-boostxe2x80x9d delivered by means of external-beam radiation therapy; (6) with a wide variety of seeds available, many cancers can be more effectivley managed by brachytherapy alone; (7) a wide variety of radionuclides with energies varying from very low to very high can be incorporated into composite intracavitary sources by sealing multiple multilayered radioactive microspheres of one or several types into an appropriate container; (8) use of low energy intracavitary sources composed of low energy multilayered radioactive microspheres allow selective shielding of adjacent vital structures such as rectum and bladder using relatively thin high atomic weight foils placed over the intracavitary sources or source holders.
The ribbons, wire, plaques and fabric of this invention have the advantages of: (1) multiple multilayered radioactive microspheres provided on a single ribbon allow multiple multilayered radioactive microspheres to be implanted at once by a thin gauge hollow needle by pushing the multilayer radioactive microsphere ribbon out of the tissue-embedded needle with a stylet while withdrawing the needle; (2) the ribbon-multilayered radioactive microspheres of the present invention may be implanted by a very thin 21 or 22-gauge needle; (3) the fabric of this invention self-adheres to the tissues over which it is placed and may be either tissue-absorbable or non-tissue absorbable; (4) the use of a fabric containing multiple multilayered radioactive microspheres allows rapid surgical implantation of multiple seeds without need of interstitial needles or a seed gun; and (5) very thin plaques such as optical plaques can be contoured have the appropriate strength and appropriate intensity for effective treatment.